The estrogen receptor (ER) is a transcriptional factor that drives both the proliferation and growth of luminal type breast cancers and is the major target of current endocrine-based adjuvant therapies for breast cancer. Although such endocrine therapies are very effective, a major clinical limitation is the development of acquired endocrine resistance that diminishes therapeutic efficacy and increases mortality from breast cancer. Nevertheless, pre-clinical and clinical observations suggest that even following the development of such endocrine resistance, ER signaling continues to exert a pivotal role in tumor progression. We have recently detected ESR1 (the gene that encodes for ER) mutations in 14% of patients ER positive metastatic breast cancer. The central hypothesis of this proposal is that the ESR1 mutations are drivers of endocrine resistance and increased invasiveness and targeting of the mutant estrogen receptor with improved estrogen receptor modulators (SERMs) or degraders combined with the inhibition of other key proteins of the ER signaling axis, will lead to tumor regression and eventually improved clinical outcomes. To test this hypothesis we will: 1. Establish new in-vitro and in- vivo models to expand our studies on the functional roles of the ESR1 mutations in endocrine resistance and invasiveness 2. Delineate the transcriptional network activated by the ER mutants to identify potential targets to overcome endocrine resistance 3. Test the combination of bazedoxifene, a third generation SERM, together with palbociclib, a CDK4/6 inhibitor, to effectively target the mutant estrogen receptors and circumvent endocrine resistant tumor growth. These studies have the potential to be directly translated to the clinical arena and improve the treatment of endocrine resistant breast cancer.